Insulin Secretory Defect in Zucker fa/fa Rats Is Improved by Ameliorating Insulin Resistance

  1. Martin D Meglasson
  1. Departments of Endocrine Pharmacology and Metabolism Upjohn Laboratories, Kalamazoo, Michigan
  2. Investigational Toxicology Upjohn Laboratories, Kalamazoo, Michigan
  1. Address correspondence and reprint requests to Dr. Martin D. Meglasson, Department of Endocrine Pharmacology and Metabolism, Upjohn Laboratories, 301 Henrietta St., Kalamazoo, MI 49001.

Abstract

The role of insulin resistance in the impaired glucosestimulated insulin release of Zucker fatty rats was investigated using the insulin-sensitizing thiazolidinedione drug pioglitazone. Fatty rats had fasting hyperinsulinemia yet a blunted secretory response to intravenous glucose compared with lean age-matched controls. Islets from fatty rats secreted less insulin (based on islet DNA) in response to high glucose than islets from lean rats but secreted normal amounts of insulin when tolbutamide or α-ketoisocaproic acid (α-KIC) was the stimulus. Administering pioglitazone for 9 days diminished basal hyperinsulinemia and increased the insulin response to high glucose by fatty rats but not by lean controls. Pioglitazone pretreatment augmented the secretory response by isolated islets to high glucose, α-KIC, and tolbutamide. Augmentation of islet insulin release was not associated with reduced plasma glucose concentration, suggesting that altered glycemia was not involved. Pancreas and islet insulin content was greater in fatty rats than in lean controls and was decreased by pioglitazone; hence, insulin stores and glucose-stimulated insulin release did not correlate. Pioglitazone treatment did not affect the rate of islet glucose usage or ATP/ADP in the presence of 2.75 or 16 mmol/1 glucose. These data indicate that ameliorating insulin resistance reverses defective glucosestimulated insulin release by Zucker fa/fa rats. After pioglitazone administration, insulin secretion may be augmented by increased generation of a metabolic coupling factor from glucose or at a later step in the secretory process that is common to both glucose and nonglucose secretagogues.

  • Received August 16, 1994.
  • Revision received April 20, 1995.
  • Accepted April 20, 1995.
| Table of Contents